Microcephaly refers to a condition in which the human brain fails to achieve normal size. It is associated with mental retardation, developmental delay, neuromotor disability, and epilepsy. Therefore, it is a major cause of neurological disability in children. The causes of microcephaly are diverse, but many microcephaly syndromes are inherited as autosomal recessive conditions. Thus, genetic microcephaly is particularly prevalent in countries and regions where consanguineous marriages are common. Tunisia is one such country, as the proportion of consanguineous marriages in Tunisia is estimated as 33%. The majority of the Tunisian population is made up of Arabs, but the genetic make up of Tunisia is unique among the Arab countries because of its long historical role as a crossroad between East and West, and among Europe, Africa and Asia. Therefore, by studying genetic microcephaly in the Tunisian population, we are likely to identify novel genetic causes of microcephaly. In addition, through the genetic epidemiological analysis of genetic microcephaly syndromes in Tunisia, we will be able to benefit the affected individuals and their families by developing improved genetic diagnosis and counseling. This work will be performed in collaboration with the Department of Genetics at Hospital Charles Nicolle in Tunis, which is the largest genetics center in the country. We will enroll the patients and families with autosomal recessive microcephaly through their clinic, and perform genetic analysis of the patients by utilizing the method of homozygosity mapping with state-of-the-art high density SNP genome-wide screening. One of the major goals of this project is to develop genetic research capacity at Hospital Charles Nicolle, and a large part of work will be carried out there, with assistance from our group in the U.S. PUBLIC HEALTH RELEVANCE: Genetic microcephaly is a group of disorders in which the human brain fails to achieve normal size, and is a major cause of neurological disability in children. It is more commonly seen in countries and regions where marriages between relatives are common, such as Tunisia, but is seen everywhere including the U.S. The unique population structure of Tunisia allows the identification of novel microcephaly genes, and once the causative genes are found, children with microcephaly and their families in the U.S. also benefit from DNA-based diagnostic testing. Thus, the results of our work will help improve the genetic diagnosis and genetic counseling of this group of devastating disorders, and by unraveling the basic mechanisms of brain development, it is hoped to pave the way toward eventual treatment of this and other neurodevelopmental disorders.